Opioid Drug Design Flashcards
4 Aims of opioid drug design:
Maintain/increase activity
Lower side-effects
Increase oral activity
Add/find extra binding groups
Oxymorphine:
Has – x the activity
Is an – extension at position number –
Increased activity may be due to…
2.5
OH
14
extra Hydrogen bonding interaction with receptor.
N-substituent extension:
A — substituent reaches a — binding region.
When N R group is substituted for CH2-C-CH3, the compound acts as an —. There is failure to activate —
Useful to counteract –/–
Useful for treating addiction to – or –
Phenethyl hydrophobic antagonist receptors morphine overdose morphine heroin
2 examples of morphine antagonists:
The latter is given to people who…
Naloxone
Naltrexone
Need weaning off morphine or heroin
Nalorphine: it is an --- to morphine used to treat... It is also a weak --- This indicates there are multiple --- receptors Its an -- for some receptors, and an -- at others It is a non-addictive --- It has --- side-effects
antagonist morphine overdose agonist opioid agonist antagonist analgesic hallucinogenic
Example of antagonist with agonist activity.. Similar activity to -- It has low -- liability No --- effect Not --- active
Nalbuphine morhpine addiction psychotomimetic orally
Simplification Strategies (3)
Remove non-essential functional groups
remove rings
remove asymmetric centres
Properties of simplified analogues: (4)
Easier, quicker, cheaper to make
may increase/decrease activity
May interact differently with receptor
May increase or decrease side-effects
Levorphanol: The -- ring is removed and there is a -- group attached to the N activity increased by --x Increased --/-- Active when administered --- Duration longer/shorter? Less/more metabolism in liver
D Methyl 5 side-effects orally longer less
Morphinans have the – ring removed
D
N-methylmorphinan still has – activity despite lack of – group
analgesic
phenol
Morphinans are more — and — lasting than their morphine counterparts, but also have higher – and comparable — characteristics.
Changes carried out on morphinans have same — effect as those carried out on morphine, This implies the same— interactions and —.
Simpler molecules are easier to —
potent longer toxicity dependance biological receptor binding synthesise
Morphinans with regards to removal of C ring:
With 6,7 Benzomorphans, the presence of a – group is and added complication, so was decided that it was best to look for more – structures.
Rings – and – are not essential for — activity
Analgesia and addiction are not necessarily —
These are clinically — compounds with reasonable – activity, with less – liability and –
They are simpler to —
Interact with –/–/– in the same way as –
phenol simple C D analgesic co-existent useful analgesic addiction tolerance synthesise target binding sites morphine
4-phenylpiperidines:
— group not necessary for —
The – group is a binding group that is not present in previous — classes.
N-Allyl or cyclopropyl groups show no — properties
Implies different – interactions.
More — allows potential for different – modes
very easy/hard to synthesise.
phenol activity ester structural antagonist receptor flexibility binding easy
Methadone: It is a useful -- and is --- active. It is slightly --- 2 side-effects: Has less severe -- and -- effects Minimal -- effects and less severe --/-- Used as a sub for morphine and heroin to treat -- Its a flexible molecule so has a different -- mode to morphine
analgesic orally sedative depressed respiration dependence potential emetic constipation euphoric side effects addicts binding
Rigidification strategy: Less --- structures More active if -- is retained possibly less --/-- Better -- absorption Less/more easy to make
flexible conformation side effects oral less
Thebaine is inactive, but is a useful starting material for —/—
rigid opiates
Etorphine is —x more active, used as a sedative for –
10,000
big game animals
